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WO2017046756A1 - Esters de céfixime proxétil et axétil - Google Patents

Esters de céfixime proxétil et axétil Download PDF

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Publication number
WO2017046756A1
WO2017046756A1 PCT/IB2016/055533 IB2016055533W WO2017046756A1 WO 2017046756 A1 WO2017046756 A1 WO 2017046756A1 IB 2016055533 W IB2016055533 W IB 2016055533W WO 2017046756 A1 WO2017046756 A1 WO 2017046756A1
Authority
WO
WIPO (PCT)
Prior art keywords
cefixime
pharmaceutically acceptable
proxetil
acceptable salt
formula
Prior art date
Application number
PCT/IB2016/055533
Other languages
English (en)
Inventor
Avinash K. NANGIA
Girij Pal Singh
Anurag TRIVEDI
Sunil MURKUTE
Hitendra MAHETA
Original Assignee
Lupin Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lupin Limited filed Critical Lupin Limited
Publication of WO2017046756A1 publication Critical patent/WO2017046756A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to proxetil and axetil esters of cefixime and their treating bacterial infections.
  • Cefixime is a broad spectrum third generation cephalosporin antibiotic. It is useful for the treatment of a number of bacterial infections and is chemically known as (6R,7R)-7- ⁇ [2- (2-amino-l,3-thiazol-4-yl)-2-(carboxymethoxyimino)-acetyl]amino ⁇ -3-ethenyl-8-oxo-5- thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid having chemical structure of formula I.
  • the present invention relates to compound of formula II
  • the present invention further relates to substantially pure cefixime proxetil or a pharmaceutically acceptable salt thereof.
  • the present invention further relates to substantially pure cefixime axetil or a pharmaceutically acceptable salt thereof.
  • cefixime proxetil cefixime 1-methyl ethoxycarbonyloxy ethyl ester
  • cefixime axetil cefixime acetoxy ethyl ester
  • a pharmaceutically acceptable salt thereof as a valuable prodrug ester of cefixime, particularly suitable for oral and parenteral administration in various animal species and in man for treatment of infections caused by gram-positive and gram-negative bacteria.
  • salts denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful.
  • Salts of the compound of the Formula II may be formed, for example, by reacting a compound of Formula II with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates,
  • camphorsulfonates fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould,
  • Exemplary basic salts include alkali metal salts such as sodium or potassium salts; alkaline -earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine or procaine salts; aralkyl amine salts such as N,N- dibenzylethylenediamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium
  • the compound of Formula (II) contain asymmetric or chiral center, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compound of Formula (II) as well as mixtures thereof, including racemic mixtures, form part of the present invention. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the present invention further relates to a process for the preparation of cefixime proxetil, wherein the process comprises,
  • the present invention further relates to a process for the preparation of cefixime axetil, wherein the process comprises,
  • Halo/ halide means halogen such as iodo, chloro or bromo.
  • the reaction can be carried out in the presence of a solvent which is inert under the reaction conditions, for example dimethylacetamide, dimethylformamide,
  • the reaction can be carried out in the presence of base.
  • the base may be organic or inorganic base or mixture thereof.
  • Organic base may be for example pyridine, N- methylpiperidine, N-methyl pyrrolidine, triethylamine, tributylamine, N, N-dimethylaniline, dicyclohexylamine, N-methyl morpholine, collidine, lutidine, picoline, quinoline, isoquinoline, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU).
  • Inorganic base may be for example sodium carbonate, potassium carbonate and sodium bicarbonate.
  • the reaction can be carried out at a temperature in the range -50 ° to 100 °C, preferably at -10 °C to 50 °C, most preferably at about -10°C to about 0°C.
  • the product may be purified by gravity column chromatography, flash chromatography, preparative HPLC.
  • substantially pure means that the compound is at least 90% pure as determined by HPLC analysis.
  • the present invention provides cefixime proxetil that is substantially pure.
  • cefixime proxetil of present invention has a purity of more than 90 % by HPLC analysis.
  • cefixime proxetil of present invention has a purity of more than 95 % by HPLC analysis. In another embodiment, cefixime proxetil of present invention has a purity of more than 97 % by HPLC analysis.
  • cefixime proxetil of present invention has a purity of more than 99 % by HPLC analysis.
  • the present invention provides cefixime proxetil that is substantially free from the compound of formula III as an impurity.
  • 'Substantially free' means less than 1% of the compound of formula III is present as an impurity.
  • the present invention provides cefixime proxetil containing less than 0.5 % of the compound of formula III as an impurity. In another embodiment, the present invention provides cefixime proxetil containing less than 0.2 % of the compound of formula III as an impurity.
  • the present invention provides cefixime proxetil containing less than 0.1 % of the compound of formula III as an impurity.
  • the present invention provides cefixime axetil that is substantially pure.
  • cefixime axetil of present invention has a purity of more than 90 % by HPLC analysis.
  • cefixime axetil of present invention has a purity of more than 95 % by HPLC analysis.
  • the present invention provides cefixime axetil that is
  • 'Substantially free' means less than 1% of the compound of formula IV is present as an impurity.
  • the present invention provides cefixime axetil containing less than 0.5 % of the compound of formula IV as an impurity.
  • the present invention provides cefixime axetil containing less than 0.2 % of the compound of formula IV as an impurity. In another embodiment, the present invention provides cefixime axetil containing less than 0.1 % of the compound of formula IV as an impurity.
  • the present invention further relates to a process for the preparation of amorphous form of compound of formula II, wherein the process comprises,
  • the solvent may comprise at least one of water, alcohol (such as methanol, ethanol, propanol, isopropanol), nitrile (such as acetonitrile), N, N-dimethylformamide, dimethylsulphoxide, tetrahydrofuran, ketone (such as acetone), ester (such as ethyl acetate), and chlorinated hydrocarbons (such as dichloromethane).
  • alcohol such as methanol, ethanol, propanol, isopropanol
  • nitrile such as acetonitrile
  • N, N-dimethylformamide such as dimethylsulphoxide, tetrahydrofuran
  • ketone such as acetone
  • ester such as ethyl acetate
  • chlorinated hydrocarbons such as dichloromethane
  • the suitable separation technique may comprise at least one of lyophilization (freeze drying), spray drying, thin film drying (rotary evaporation)and agitated thin film drying.
  • the present invention provides an amorphous cefixime proxetil.
  • the present invention provides an amorphous cefixime proxetil which is characterized by X-ray diffraction spectrum substantially as shown in figure 1. In another embodiment, the present invention provides an amorphous cefixime axetil.
  • the present invention provides an amorphous cefixime axetil which is characterized by X-ray diffraction spectrum substantially as shown in figure 2.
  • the compound of formula II or pharmaceutically acceptable salt thereof may be formulated as compositions for oral or parenteral administration in conventional manner, with the aid of any necessary pharmaceutical carriers or diluents.
  • the compositions are conveniently prepared as tablets, capsules or sachets, advantageously in unit dose form, and may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants and wetting agents. Tablets may be coated in conventional manner.
  • the active compounds may further be formulated in rectal compositions such as suppositories or retention enemas.
  • compositions may contain from 0.1-99% of compound of formula II or
  • compositions in dosage unit form conveniently contain 50-500 mg of the active ingredient (calculated as cefixime).
  • doseses employed for adult human treatment will typically be in the range 100-1000 mg per day, e.g. 400 mg per day, (calculated as cefixime), although the precise dose will depend on the frequency of administration.
  • Mobile phase A 0.05 M ammonium acetate in water. 50 ml buffer replaced with methanol and adjusted to pH 4.2 with orthophosphoric acid.
  • Mobile phase B 0.05 M ammonium acetate in water. 500 ml buffer replaced with methanol and adjusted to pH 4.2 with orthophosphoric acid. Injection volume: 20 ⁇ ..
  • Sample preparation 5 mg in 5 ml diluent.
  • Diluent is prepared by mixing a and b in ratio of 39:61.
  • XRPD X-ray powder diffraction spectrum
  • IR (in KBr)cm _1 3430, 3202, 2986, 2937, 1760, 1672, 1617, 1584, 1537, 1425, 1376, 1315, 1277, 1220, 1159, 1099, 1075, 1039, 995, 905, 813, 788, 741.
  • Sample preparation 4 g + 40 ml methanol + 20 ml mobile phase A. 1.5 ml injected.
  • IR (in KBr)cm 1 3430,1775, 1666, 1584, 1536, 1425, 1376, 1315, 1237, 1212, 1158, 1074, 1039, 995, 944, 864, 813, 726.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

La présente invention concerne un composé de formule II (II) dans laquelle R = -OCH(CH3)2, -CH3; ou un sel pharmaceutiquement acceptable de celui-ci. La présente invention concerne en outre du céfixime proxétil essentiellement pur; du céfixime axétil essentiellement pur et le sel pharmaceutiquement acceptable de ceux-ci.
PCT/IB2016/055533 2015-09-18 2016-09-16 Esters de céfixime proxétil et axétil WO2017046756A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3573MU2015 2015-09-18
IN3573/MUM/2015 2015-09-18

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WO2017046756A1 true WO2017046756A1 (fr) 2017-03-23

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111606925A (zh) * 2020-07-01 2020-09-01 心邀（深圳）生物科技有限公司 一种头孢克肟△3异构体杂质的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4423213A (en) * 1979-11-19 1983-12-27 Fujisawa Pharmaceutical Co., Ltd. 7-Acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof
EP0186586A2 (fr) * 1984-12-20 1986-07-02 Meiji Seika Kaisha Ltd. Dérivés céphem et leur production
WO2001009143A1 (fr) * 1999-07-30 2001-02-08 Ranbaxy Laboratories Limited Forme amorphe amelioree de cefpodoxime proxetil
EP1619198A1 (fr) * 2004-07-22 2006-01-25 Nanomaterials Technology Pte Ltd Cefuroxim acetil et un procédé pour sa préparation
WO2007017895A2 (fr) * 2005-05-05 2007-02-15 Lupin Limited Compositions pharmaceutiques stabilisees de cephalosporines

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4423213A (en) * 1979-11-19 1983-12-27 Fujisawa Pharmaceutical Co., Ltd. 7-Acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof
EP0186586A2 (fr) * 1984-12-20 1986-07-02 Meiji Seika Kaisha Ltd. Dérivés céphem et leur production
WO2001009143A1 (fr) * 1999-07-30 2001-02-08 Ranbaxy Laboratories Limited Forme amorphe amelioree de cefpodoxime proxetil
EP1619198A1 (fr) * 2004-07-22 2006-01-25 Nanomaterials Technology Pte Ltd Cefuroxim acetil et un procédé pour sa préparation
WO2007017895A2 (fr) * 2005-05-05 2007-02-15 Lupin Limited Compositions pharmaceutiques stabilisees de cephalosporines

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"The Orange Book", FOOD & DRUG ADMINISTRATION
ANDERSON ET AL.: "The Practice of Medicinal Chemistry", 1996, ACADEMIC PRESS
P. GOULD, INTERNATIONAL J. OF PHARMACEUTICS, vol. 33, 1986, pages 201 - 217
P. STAHL ET AL.: "Handbook of Pharmaceutical Salts. Properties, Selection and Use", 2002, WILEY-VCH
S. BERGE ET AL., JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 66, no. 1, 1977, pages 1 - 19

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111606925A (zh) * 2020-07-01 2020-09-01 心邀（深圳）生物科技有限公司 一种头孢克肟△3异构体杂质的制备方法

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